DART: Success Story in High-Grade Neuroendocrine Carcinomas

Alexander M. Castellino, PhD

April 02, 2019

ATLANTA — Patients with rare, high-grade neuroendocrine carcinomas showed good clinical responses to treatment with a combination of two immunotherapies — ipilimumab (Yervoy, Bristol-Myers Squibb) and nivolumab (Opdivo, Bristol-Myers Squibb).

The new results come from the South West Oncology Group (SWOG) S1609 Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART) study. They were reported here at the American Association for Cancer Research (AACR) 2019 (abstract CT039).

Dr Sandip Patel

"We were pleasantly surprised to see that patients with high-grade neuroendocrine carcinomas derived benefit from a combination of the two immune checkpoint inhibitors," presenter Sandip Patel, MD, medical oncologist with Moores Cancer Center at the University of California San Diego Health, told Medscape Medical News. "Regardless of the site of origin, overall response rates [ORRs] are on the order of 40%," he added.

He explained that current treatment options for patients with high-grade neuroendocrine carcinomas are generally limited to aggressive chemotherapy regimens. "This is an exciting finding for this patient population and is the first new therapy outside of chemotherapy for these patients," he said.

The combination of ipilimumab and nivolumab is already used in the treatment of melanoma and was approved in 2018 for use in the treatment of kidney cancer.

Dual Checkpoint Blockade Advances Treatment Options

Approached for comment by Medscape Medical News, Namrata Vijayvergia, MD, assistant professor at Fox Chase Cancer Center in Philadelphia, Pennsylvania, who treats neuroendocrine cancers, said: "This is a promising study. High-grade neuroendocrine cancer is a disease where patients have very limited options after failure of first-line chemotherapy." She pointed out that response rates in this setting are typically between 10% and 20% with regular therapy.

With first-line chemotherapy, typically chosen on the basis of whether tumors are well or poorly defined, response rates are between 40% and 50%, Vijayvergia noted. "But responses are not durable, and patients progress and require second- and third-line therapies," she said.

"In recent years, several new treatment options have been developed for neuroendocrine tumors, but few options have led to durable improvements in outcome once these cancers become more aggressive," Manish Shah, MD, gastrointestinal oncologist at Weill Cornell Medicine and New York–Presbyterian Hospital, New York City, told Medscape Medical News.

Vijayvergia explained that because studies have not typically been undertaken in rare diseases such as neuroendocrine cancers, combinations that have worked in small cell lung cancer are extrapolated to high-grade neuroendocrine carcinomas, especially those of extrapulmonary origin. She cited as an example the combination of atezolizumab (Tecentriq, Genentech) with carboplatin and etoposide, which was recently approved for treatment of small cell lung cancer and is now being explored in the treatment of high-grade neuroendocrine carcinomas of extrapulmonary origin.

"The excitement around immunotherapy is that, with education and activation of the immune system, the patient's own immunity may be able to control the cancer and possibly even eradicate it," she added.

However, Vijayvergia noted that three recent trials with single-agent checkpoint blockade, including one from their group, failed to deliver clinical benefits for patients with neuroendocrine cancers. "These trials were in neuroendocrine cancers of extrapulmonary origin," she said.

She speculated that with single-agent checkpoint blockade, tumors develop an escape mechanism, which is circumvented with dual blockade. However, study investigator Patel said it is currently difficult to speculate why treatment with dual immunotherapeutic agents works whereas single-agent treatments fail.

Study Details

DART is an ongoing phase 2 basket trial. Multiple cohorts of patients with rare tumors received ipilimumab 1 mg/kg every 6 weeks and nivolumab 240 mg every 2 weeks.

The results that were reported at the AACR meeting are from the neuroendocrine cohort only and did not include patients with pancreatic neuroendocrine tumors who are being accrued into a separate cohort.

Patel reported data for 32 patients in the neuroendocrine cohort, 18 of whom (56%) had high-grade disease. The most common sites were gastrointestinal (47%) and lung (19%). Patients had received a median of two prior lines of therapy.

Responses reported in the overall population were seen only in patients with high-grade carcinomas (ORR, 44%); none were seen in patients with low-grade tumors.

Patel noted that the responses in the high-grade tumors were seen across the group, regardless of tumor origin. For pulmonary high-grade tumors, the ORR was 66% (2 of 3 patients); for nonpulmonary high-grade tumors, the ORR was 40% (6 of 15 patients); and for high-grade nonpancreatic gastrointestinal tumors, the ORR was 25% (2 of 8 patients).

Median progression-free survival was 30% at 6 months. The median overall survival was 11 months.

Asked why low- or intermediate-grade tumors did not show responses, Patel said it was difficult to explain. However, he noted that high-grade carcinomas have a high mutational burden, which is perhaps why they respond to dual checkpoint blockade.

He also suggested that low- and intermediate-grade neuroendocrine tumors may be different biologically — the infiltration of immune cells may be low, they may have a low mutational burden, or specific mutations may be absent. He explained that translational studies will be undertaken in the samples that have been banked to understand why patients with high-grade neuroendocrine carcinomas respond to dual immune checkpoint inhibition.

The most common adverse events seen with the combination of ipilimumad and nivolumab were fatigue (30%) and nausea (27%). The most common immune-related adverse events (any grade) were hyperthyroidism (31.3%) and elevations in levels of aspartate aminotransferate (AST) (25%). The most common grade 3 or 4 adverse events were elevations in levels of alanine aminotransferase (9%) and AST (6.3%). High-grade colitis was reported in 6.2% of patients. No deaths were reported.

"These data suggest that immunotherapy has great potential in this population and may yield yet another option for these patients, one that may be durable and compelling," Shah said when approached for comment.

Patel pointed out the limitations of the study. There was no central pathology review to determine organ of origin. In addition, the analysis of response rates based on high grade vs intermediate or low grade was not prespecified.

However, he was upbeat that these data will be confirmed. "Based on this study, SWOG S1609 DART is accruing a new cohort of patients with only high-grade neuroendocrine carcinomas," he said.

The NCI-Funded Basket Trial in Rare Tumors Busts a Myth

Patel explained that the SWOG S1609 DART trial is a basket trial that is accruing more than 37 cohorts of patients with cancers of rare histologies.

"SWOG S1609 DART is the first major effort to study rare tumors," Patel said. He explained that historically, there has been a bias against undertaking trials for patients with rare tumors. He noted that 62% of the patients across all the cohorts were treated in the community setting. In addition, he noted that the 560 patients in all 37 cohorts were enrolled in 2 years. "The 32 neuroendocrine patients were enrolled in 3 months," he said.

"Our data are busting the myth about rare tumor clinical trials not being feasible," Patel said.

The DART study is funded by the National Institutes of Health through National Cancer Institute grant awards and in part by Bristol-Myers Squibb. Patel reports receiving grants from Bristol-Myers Squibb and personal fees from Bristol-Myers Squibb during the conduct of the study; grants from Eli Lilly, Incyte, AstraZeneca/MedImmune, Merck, Pfizer, Roche/Genentech, Xcovery, Fate Therapeutics, Genocea, and Iovance; and personal fees from AstraZeneca, Illumina, Tempus, and Novartis. Vijayvergia consults with Novartis and receives research support from Merck. Shah has received research funding from Merck and Bristol-Myers Squibb.

American Association for Cancer Research (AACR) 2019: Abstract CT039. Presented March 31, 2019.

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